Major depressive disorder (MDD) is a leading cause of disability in the world. Treatment-Resistant Depression (TRD) causes the majority of MDD's disability. Strikingly, 50% of individuals with MDD will fail to remit with two adequate trials of antidepressant medications, thus suffering TRD. Current pharmacological and psychotherapeutic treatment strategies for TRD are limited in effectiveness so new techniques are needed. This grant is a randomized, controlled trial of Mindfulness-Based Cognitive Therapy (MBCT) for the TRD population. MBCT is a new technique that has previously been found effective for prevention of relapse in individuals in complete remission. MBCT is a group-based, 8-week intervention that uses mindfulness meditation as its core therapeutic ingredient. It teaches people to have a different relationship to depressive thoughts and feelings. Three open trials of MBCT, two pilot studies comparing MBCT to Treatment-as-Usual (TAU), and our pilot data, have found MBCT to be effective for TRD. This study will use an active control condition, the Health- Enhancement Program (HEP), which was specifically developed to serve as a credible control for mindfulness interventions. We plan to identify 124 patients with MDD who have failed two or more adequate antidepressant trials documented with the Antidepressant Treatment History Form software. We will then randomly assign patients to two groups: MBCT+TAU or HEP+TAU. We anticipate 100 patients will complete treatment. All 124 patients who enroll in the study will undergo follow-up assessments at 6 and 12 months following the 8 week intervention. The specific aim of this study is to determine the acute efficacy of MBCT in reducing depression in adults with TRD. The study will test the hypotheses that MBCT+TAU is more effective than HEP+TAU in reducing depressive symptoms and enhancing remission and response rates using the Hamilton Rating Scale for Depression over a period of 8 weeks. We will also conduct a series of secondary hypotheses and analyses to evaluate if MBCT+TAU is more effective than HEP+TAU in reducing disability and improving quality of life. In addition we will also evaluate potential mediators of MBCT efficacy: enhanced mindfulness, decreased rumination, and decreased experiential avoidance. Although this is an acute treatment trial of MBCT in TRD, we will also evaluate whether beneficial effects of 8 weeks of treatment persist at 6 and 12 months. Findings from this study would have clear public health significance because MBCT could prove to be an effective treatment for TRD patients, reducing the suffering, disability, and medical comorbidity common in TRD. PUBLIC HEALTH RELEVANCE: Major depressive disorder is the most prevalent mental health problem in the world. This study is a randomized, controlled trial of a new adaptation of Mindfulness-Based Cognitive Therapy (MBCT), to the Treatment-Resistant Depression (TRD) population. Because TRD affects 50% of individuals treated with antidepressants, MBCT has significant potential to help reduce the suffering, disability, and medical comorbidity that often accompanies this disorder.